The invention provides compositions and methods for inhibiting laminin5beta3 gene expression and/or biological activity. Such compositions and methods find utility in the treatment of cancers, particularly of epithelial origin.
A number of cancers derive from epithelial cells, including some colon cancers and breast cancers. Laminin is a secreted protein that plays a role in normal cell function by interacting with its integrin receptors. Laminins are heterotrimeric basement membrane molecules that mediate important cell functions including adhesion, migration and differentiation. Laminin5gamma2 has been found to play a role in cell adhesion of human keratinocytes and mouse squamous carcinoma cells. (Salo, S. et al., Matrix Biol. 18:197-210, 1999.) Alteration of laminin-5 expression was reported in development of squamous cell carcinomas. (Thorup, A. K. et al., A.P.M.I.S. 106:1170-1180, 1998.) Because of the role played by proteins of the laminin family in cancer cell development, there is a need in the art for materials and methods for regulating laminin expression and function, thereby providing new methods for cancer treatment and prevention.
The present invention provides, in one embodiment, inhibitors of laminin5beta3. Inventive inhibitors include, but are not limited to, antisense molecules, ribozymes, antibodies or antibody fragments, human monoclonal antibodies, proteins or polypeptides as well as small molecules. Exemplary antisense molecules comprise at least 10, 15 or 20 consecutive nucleotides of or hybridize under stringent conditions to the nucleic acid of SEQ ID NO: 1. More preferred are antisense molecules that comprise at least 25 consecutive nucleotides of or hybridize under stringent conditions to the sequence of SEQ ID NO:1. Representative antisense molecules are provided herein as SEQ ID NO:2 and 3.
In further embodiments, compositions are provided that comprise one or more laminin5beta3 inhibitor in a pharmaceutically acceptable carrier.
Additional embodiments provide methods of decreasing laminin5beta3 gene expression or biological activity.
Each of the methods of the present invention have in common the administration of one or more inventive laminin5beta3 inhibitor to a mammalian cell.